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Blood, 1 December 2008, Vol. 112, No. 12, pp. 4628-4638. Prepublished online as a Blood First Edition Paper on September 25, 2008; DOI 10.1182/blood-2008-03-148999. This Article Full Text Full Text (PDF) Supplemental Table and Figures Additional Supplemental Figures All Versions of this Article: blood-2008-03-148999v1 112/12/4628    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kim, Y.-W. Articles by Kong, Y.-Y. Search for Related Content PubMed PubMed Citation Articles by Kim, Y.-W. Articles by Kong, Y.-Y. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Defective Notch activation in microenvironment leads to myeloproliferative disease Young-Woong Kim1, Bon-Kyoung Koo1,2, Hyun-Woo Jeong1, Mi-Jeong Yoon1, Ran Song1, Juhee Shin1, Dae-Chul Jeong3, Sun-Hee Kim4, and Young-Yun Kong1,2 1 Department of Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk; 2 School of Biological Science, College of Natural Sciences, Seoul National University, Seoul; 3 Department of Pediatrics, Catholic University of Korea, Seoul; and 4 Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea Despite the great importance of nonhematopoietic cells constituting the microenvironment for normal hematopoiesis, the cellular interactions between nonhematopoietic cells themselves are largely unknown. Using the Cre-loxP system in mice to inactivate Mind bomb-1 (Mib1), an essential component for Notch ligand endocytosis, here we show that the development of an MPD is dependent on defective Notch activation in the microenvironment. Our 2 independent Mib1 conditional knockout (CKO) mouse lines each developed a myeloproliferative disease (MPD), with gradual accumulations of immature granulocytes. The mutant mice showed hepatosplenomegaly, anemia, granulocytosis, and leukocyte infiltration in multiple organs and finally died at approximately 20 weeks of age. We were surprised to find that the transplantation of wild-type bone marrow cells into the Mib1-null microenvironment resulted in a de novo MPD. Moreover, by introducing the constitutively active intracellular domain of Notch1 in the Mib1-null background, we show that active Notch1 expression in the Mib1-null microenvironment significantly suppressed the disease progression, suggesting that the MPD development in the Mib1 CKO mice is due to defective Notch activation in the nonhematopoietic cells. These findings demonstrate that normal hematopoiesis absolutely requires Notch activation through the Notch ligand-receptor interaction between microenvironmental cells themselves and shed light on the microenvironment that fosters hematopoietic disorders. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

	Copyright © 2008 by American Society of Hematology         Online ISSN: 1528-0020